Human Genetics

, Volume 120, Issue 5, pp 633–640 | Cite as

The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model

  • Rhonda M. Clark
  • Irene De Biase
  • Anna P. Malykhina
  • Sahar Al-Mahdawi
  • Mark Pook
  • Sanjay I. Bidichandani
Original Investigation


Friedreich ataxia (FRDA) is caused by homozygosity for FXN alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence. Patients have progressive neurodegeneration of the dorsal root ganglia (DRG) and in later stages the cerebellum may be involved. The expanded GAA-TR sequence is unstable in somatic cells in vivo, and although the mechanism of instability remains unknown, we hypothesized that age-dependent and tissue-specific somatic instability may be a determinant of the progressive pathology involving DRG and cerebellum. We show that transgenic mice containing the expanded GAA-TR sequence (190 or 82 triplets) in the context of the human FXN locus show tissue-specific and age-dependent somatic instability that is compatible with this hypothesis. Small pool PCR analysis, which allows quantitative analysis of repeat instability by assaying individual transgenes in vivo, showed age-dependent expansions specifically in the cerebellum and DRG. The (GAA)190 allele showed some instability by 2 months, progressed at about 0.3–0.4 triplets per week, resulting in a significant number of expansions by 12 months. Repeat length was found to determine the age of onset of somatic instability, and the rate and magnitude of mutation. Given the low level of cerebellar instability seen by others in multiple transgenic mice with expanded CAG/CTG repeats, our data indicate that somatic instability of the GAA-TR sequence is likely mediated by unique tissue-specific factors. This mouse model will serve as a useful tool to delineate the mechanism(s) of disease-specific somatic instability in FRDA.



This research was made possible in part by grants from the National Institutes of Health (NINDS), Muscular Dystrophy Association, OCAST, and FARA to S.I.B. M.P. acknowledges support form The Wellcome Trust. I. D-B. is supported by a postdoctoral fellowship from the National Ataxia Foundation.


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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Rhonda M. Clark
    • 1
  • Irene De Biase
    • 1
  • Anna P. Malykhina
    • 2
  • Sahar Al-Mahdawi
    • 4
  • Mark Pook
    • 4
  • Sanjay I. Bidichandani
    • 1
    • 3
    • 5
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Department of PhysiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  3. 3.Department of PediatricsUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  4. 4.Department of Biosciences, School of Health Sciences and Social CareBrunel UniversityUxbridgeUK
  5. 5.Oklahoma CityUSA

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